HIV/AIDS CHALLENGE IN UGANDA

A REPORT AND PROPOSAL BY A MEDICAL STUDENT FROM MAKERERE UNIVERSITY

UGANDAEAST AFRICA

Willington Amutuhaire

Talk outline• Background• Evolution of the epidemic• History of HIV in Uganda• Epidemiological trends• Routes of transmission• National response• Impact of HIV• Prevention of HIV• HIV testing• HIV treatment• Challenges• Proposal• My Research project

BACKGROUNDGEOGRAPHICAL

LOCATION OF UGANDAUganda lies in sub-

Saharan Africa.It is a land locked

country in east Africa bordering Kenya to the east, Tanzania and Rwanda to the south, Democratic Republic of Congo to west and Sudan to the north.

Background Covers an area of

236,036 km2 with an estimated population of 30 million people and an average population growth rate of 3.2% (population secretariat Uganda 2007).

Majority of Ugandans (88%) live in rural areas where subsistence agriculture is the source of food and income.

Ugandan women preparing a meal (above) and men transporting matooke (plantain) to the market (below)

Africa carries 25% of the world’s disease burden; However she has 3% of the world’s health workers and 1% of the world’s economic resources.

(Robinson M, Clarke P Lancet 2008)

Patients with liver disease

EVOLUTION OF THE AIDS EPIDEMIC• The first AIDS cases were

identified in 1982 on the shores of Lake Victoria in the southern district of Rakai.

• Superstitions and witchcraft characterised the initial response from communities.

• The epidemic progressed very fast to other parts of the country, initially concentrating in the urban and semi-urban centres.

Map of Uganda showing Rakai district (in red)

Lake Victoria

HISTORY OF HIV IN UGANDAIn 1982 the first 2 cases

of slim disease were reported in Rakai.

In 1983, 17 more cases of slim were reported.

In 1984 slim disease was confirmed as AIDS.

In 1990 the epidemic spread from major towns to rural populations in Uganda.

TO DATE-all districts have reported AIDS. An HIV/AIDS child at Mulago

Hospital

HIV/AIDS EPIDEMIOLOGICAL TRENDS IN UGANDA

• Sub-Saharan Africa accounts for 68% of those living with HIV/AIDS globally (UNAIDS 2007).

• Uganda was among the first hard hit countries with a prevalence rate of 9% from 1987 to 1988.

• In 1992 the prevalence rate was 18.3% in rural areas and 30% in the towns.

• From 1993-2002 prevalence rate was 6%.• The current prevalence rate is 6-8%. Women

8% and 5% in men.

ROUTES OF TRANSMISSION OF HIV IN UGANDA

• Heterosexual transmission accounts for 84%.• Mother to child transmission accounts for

14%.• Contaminated blood/blood products, use of

un-sterilised needles and syringes, and use of un-sterilised instruments all account for 2%.

HIV/AIDS FUNDING IN UGaNDA• U.S Presidential Emergency plan for AIDS

Relief(PEPFAR) contributes 75%• The Global fund to fight Malaria,HIV and

Tuberculosis set up by G8 in 2002• International non governmental organisations 20%• Government of uganda allocates 5% ($ 30 m) for

HIV/AIDS• $ 1 is sufficient to buy antiretroviral therapy for

one patient per day but unfortunately majority of Ugandans can’t afford a dollar per day.

NATIONAL RESPONSE TO HIV/AIDS• Response confined to Ministry of Health 1982-

1984. • Disease viewed as witchcraft and later the

disease of the immoral.• In 1985, the national committee for the

prevention of AIDS was established.• In the same year, the first AIDS control program

in the country was established.• In 1987, HIV/AIDS was declared a public health

problem and also a socio-economic disaster that called for interventions from all sectors.

• AIDS control projects started in 12 ministries.

UGANDA AIDS COMMISSION• Established in 1992 with the following

objectives;-prevention of HIV with a focus on

children, youth and gender issues (gender based violence,).

-mitigating the health and socio-economic impact of AIDS.

-a national information base for HIV/AIDS.-capacity building and research in

HIV/AIDS.-planning, monitoring and evaluation

National HIV/AIDS programmes.

The AIDS support organisation(TASO)• Founded in 1986 by Noerine Kaleeba and 15 colleagues

most of whom have died. With the following objectives 1. Fight discrimination and stigma.2. Provide counselling services for HIV/AIDS patients and

their families.3. Complement available medical services (antiretroviral

therapy)4. Sensitise the public and promote positive attitudes

towards people with HIV/AIDS and their families.5. Provide material support to clients and their families e.g

food.6. Build and support community-based efforts initiated to

respond to the AIDS epidemic.

Makerere university HIV/AIDS projectsInfectious disease institute(IDI)

was opened in 2004 as a collaboration between Makerere University and Pfizer. It offers training, research, prevention, care and treatment services.

Makerere University Walter Reed Project. A collaboration between Makerere & Walter Reed institute of research (U.S Army) in HIV Vaccine development

Makerere - Mbarara Universities joint AIDS programme (MJAP) collaboration in Study of Effects of Antiretroviral therapy, teaching of service providers

IDI building (above) and Makerere main building (below)

• Joint clinical research centre (JCRC)Founded in 1990 as a joint project of the Ministries of Health, Defence and Makerere University.Early on, 70% of HIV patients received their Antiretroviral therapy from JCRC.

• Baylor College of Medicine Children foundation, cares for children infected or exposed to HIV, teaching and research

• Makerere-Johns Hopkins University research collaboration in Prevention of Mother to Child HIV Transmission

Baylor college of medicine (above) and JCRC ART clinic launch below

Trends in the prevalence of AIDS in Uganda3 phases:Phase 1: Rapid spread and increase

in prevalence from 1982-1991. Phase 2: Dramatic decline in

prevalence From 1992-2000 during which

period, HIV prevalence fell drastically from 15% in rural areas and over 30% in cities to around 5% in 2001.

Phase 3: Stabilisation of prevalence rate at 6-7% from 2002-2005.

Phase 4: HIV prevalence rate may be increasing again?

Reasons for Change in TrendsPhase 1 Lack of knowledge about the

disease Lack of treatmentPhase 2 Death Decline in new infections due to

behavioural change (ABC) and the sheer scale of HIV epidemic

Phase 3 Free HIV drugs.HIV is no longer

an immediate death sentencePhase 4: Economic crisis, NGOs have

cut funding and some HIV centres have closed

IMPACT OF AIDS ON UGANDA1. Death of approximately

one million people since the beginning of the epidemic.

2. Reduced life expectancy from 54.1 to 42.6 years.

3. One million orphans left behind (child headed homes).

4. Depleted labour force, reduced agricultural output and food security.

5. Weakened health sector.

An HIV/AIDS lady at her home(above) and a child headed family(below)

6. Increased poverty at the household level7. Stigma and discrimination at all levels of

society8. Increased school drop-outs due to lack of

school fees and also to care for the sick “If someone in Uganda tells you they have not

been affected by HIV/AIDS, then they are lying”

HIV prevention in UgandaUganda has always been

cited as an example of success in a continent facing a severe AIDS crisis.

The approach Uganda used has been based on ABC.

A- Abstinence B- Be faithful to your

partner(zero grazing)C- Condom useC-?Circumcision

A message on HIV prevention on a school compound (above) and an HIV sensitisation talk (below)

Prevention of Mother To Child Transmission (PMTCT)

Started in 2000 in a small number of Antenatal clinics. The programme includes;

1. Voluntary counselling and testing (VCT) for mothers attending ANC.

2. Treatment of mothers and children following positive diagnosis.

Currently 80% of pregnant mothers receive PMTCT.

A pregnant mother receiving PMTCT services at a health centre in Kampala, the capital city of Uganda

HIV testing

People lining up to test for HIV in Kampala city suburb

Uganda was the first to open Voluntary Counselling & Testing (VCT) clinic in Sub-Saharan Africa.

In 1999 VCT started in resource limited areas.

In 2007 VCT was available in 45% of health facilities.

Currently Routine Counselling & Testing (RCT) is done to everyone who comes to a health facility unless they choose to opt out.

80% of Ugandans remain unaware of their HIV status.

HIV treatment in UgandaUganda was among the first

countries in Africa to distribute life saving Antiretroviral therapy (ARVs) in 1998.

In June 2004, free ARV medication for people living with HIV was started.

Only 30% of people needing ARVs receive them due to lack of sufficient supply.

95% of ARVs funded by the U.S. through Presidential Emergency Plan For AIDS Relief (PEPFAR) and Global fund

HIV patients waiting for ARVs at Infectious disease institute Makerere University

Number of active ART sites in Uganda: 2003-2008

26

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207

305

331

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300

350

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Common Opportunistic infections• TB. Uganda is 15th

among the 22 TB High Burden Countries (HBCs). High association of TB & HIV (40-50% TB are HIV+).

• Kaposi Sarcoma(48.9 of cancers in men and 17.9 in women)

• Cryptococcus Meningitis(10-30%)

• Pneumocysts Carinii neumonia(16.5%)

• Candidaisis(80-90%)Mulago Hospital

Cutaneous KS(above) and Oral Candidiasis(below)

Ashinaga Uganda - Caring for AIDS Patients

• Started in 2000 with the president, Museveni, as its patron.

• Supports 1300 orphans• Education for AIDS

orphans• Offers emotional and

psychological support• HIV prevention through

counselling and community education

Challenges• HIV prevalence is high among the married, this

increases transmission to children.• Religious leaders preach against condom use.• Some religious groups discourage use of

antiretroviral therapy and encourage patients to concentrate on prayers.

• 95% of ART is donor funded.• Political instability especially in northern Uganda.• Limited resources for research about HIV in Uganda.• Corruption: Global fund suspended funding in 2005

due to financial mismanagemant.• Economic crisis. Reduced funding by international

organisationsS

ProposalCollaboration between Universities in Africa

and U.S.A both in research and student exchange programs is necessary, particularly in basic science research in HIV where little basic research has been done in Africa

To establish a basic HIV/AIDS research centre in Africa in future.

To accelerate basic reseach to deveop new and more effective antiretroviral drugs that are affordable to HIV/AIDS patients.

BACKGROUND: HIV –ASSOCIATED METABOLIC SYNDROME

The introduction of highly active antiretroviral therapy (HAART) has drastically improved the life expectancy of patients with acquired immunodeficiency syndrome (AIDS), by reducing infection-related mortality. There has, however, been an increasing adverse events,such as metabolic derangements, related to HAART, especially with regimens containing protease inhibitors. These metabolic complications include insulin resistance, diabetes mellitus, dyslipidemia and lipodystrophy. All of these complications are associated with increased risk for atherosclerosis and cardiovascular disease

Research Project

Background: A Role of Tat in HIV associated metabolic syndrome

The etiology of human immunodeficiency virus (HIV)-associated metabolic syndrome appears to be multifactorial. Other than the anti-viral drugs, HIV-1 infection itself, including virally encoded molecule, Tat (Transactivator of transcription), has been proposed as a major contributor to the development of these pathologic changes and/or the vulnerability of patients to the adverse effects of HAART.

The Human immunodeficiency virus type 1 (HIV 1) Tat protein is also a major viral transactivator required for HIV replication.

Nonetheless, neither the approach nor the management of the HIV patient with metabolic syndrome has been established

BACKGROUND: Sirt1 and Tat in HIV infectionSirt1 is NAD+-dependent deacetylase and the closest mammalian

homologue of the yeast longevity gene, Sir2 (silent information regulator 2). Sirt1 plays important roles in metabolism, as well as DNA repair, transcriptional regulation and apoptosis. Sirt1 deacetylates a variety of substrates, including p53, PPAR-γ, FOXOs and NF-κB. Importantly, activation of Sirt1 improves insulin sensitivity and ameliorates obesity-induced diabetes in mice. The clinical trial is under way to evaluate the efficacy and safety of Sirt1 activator in patients with type 2 diabetes.

A previous study has shown that Tat binds to the catalytic domain of Sirt1 and inhibits the deacetylase activity of Sirt1 and that Sirt1 deacetylates Tat and inhibits the function of Tat

Sirt1 Tat

In HIV1 Infection:

A Novel Drug candidate Compound A can block the inhibition of Sirt1 by Tat and can inhibit Tat activity by enhancing Sirt1 –mediated deacetylation of Tat.

Sirt1 activity

Tat

Insulin resistance Promotion of HIV replication, aggravation of HIV related symptoms

Sirt1 activityTat

activity

Compound A

AIM: To identify a compound which can block the binding of Tat to Sirt1

METHODS: Cos-7 cells were co-transfected with HA-Tat and Flag-Sirt1; the cells were then treated with different concentrations of compound A

Protein expression of Sirt1 and Tat was assayed by western blotting using Anti-Flag antibody and Anti-HA antibody

The effect of Compound A on Sirt1 activity and Sirt1-Tat interaction was determined by western blotting using Anti-acetyl lysine antibody and immunoprecipitation using Anti-flag antibody respectively

Immunoprecipitation with Anti-Flag antibody of cell-lysate co transfected with Sirt1-Flag and Tat-HA

IgG heavy chain

IgG light chain

HA-Tat

RESULTS:Western blotting witha) Anti-Flag antibody

Flag-Sirt1

b) Ant-HA antibody

HA-Tat

1 2 3 4

1 2 3 4

Compound A reduced acetylation of Tat presumably by increasing Sirt1 mediated deacetylation in TSA –treated cells

Compound A

TSA(0.3uM) - + + +

Acetylated Tat

KEY FINDINGS:1.Compound A decreased Tat acetylation in a

dose dependent manner in TSA treated cells.2.Compound A blocked the binding of Tat to

sirt1.DISCUSSION: Compound A and its derivatives which

can block the binding of of Tat to Sirt1 while reducing the acetylation of Tat may be a potential drug candidate to prevent and/ treat HIV infection and HIV –related metabolic syndrome by inhibiting Tat activity while activating Sirt1.

Acknowlegement1.Endocrine society for the sponsorship2.My mentor: Prof Masao Kaneki3.Faculty of Medicine Makerere University

Thank you for listening

Welcome to Kampala, Capital city of Uganda